The thrombin receptor is a unique member of the seven trans-membrane G-protein coupled receptor superfamily. The receptor is activated by the thrombin endopeptidase which mediates cleavage of the N-terminal extracellular domain of the receptor to generate a new N-terminus. This newly generated N-terminus binds to the extracellular ligand binding domain, in what amounts to an intramolecular cyclization reaction, that activates the G-protein coupled signalling cascade. We have shown that the hexapeptide NH2-SFLLRE-CONH2, corresponding to the six amino acids of receptor N-terminus following thrombin cleavage, functions as an agonist for receptor activation. Using synthetic organic and peptidomimetic chemistry, we are learning how this peptide agonist activates the thrombin receptor. We have synthesized a number of conformationally constrained peptidomimetic compounds to the probe the geometric requirements of ligand binding. Results from cyclic peptides, as well as D-and N-alpha methyl amino acid constrained linear peptides suggest that the hexapeptide binds the receptor in an extended conformation. We are currently developing new synthetic methodology that will allow us to enforce an extended peptide conformation on a non-peptidic molecular framework. We are also pursuing structural studies with NMR to elucidate the solution structure of our conformationally constrained agonists.